Trisubstituted 3,4-dihydro-1h-isoquinolin compound, process for its preparation, and its use

ABSTRACT

The present invention relates to the compound of formula 7*acetate (see below), a process for its preparation, and its use

The present invention relates to a compound of formula 7*acetate (seebelow), a process for its preparation, and its use for the preparationof the compound of formula I.

Further, the present invention relates to a new process for thepreparation of almorexant hydrochloride, i.e. the tetra-substituted3,4-dihydro-1H-isoquinoline compound of formula I*HCl, and newintermediates.

Almorexant is known from WO 2005/118548 and Nat. Med. (2007), 13,150-155 and is especially useful as orexin receptor antagonist. It canbe obtained through a multiple-step synthesis. The key-intermediate inthe synthesis of almorexant is the 1-substituted3,4-dihydro-1H-isoquinoline derivative of formula 7. Accordingly,almorexant can be prepared by cyclisation of N-phenethyl-propionamidewith POCl₃, followed by enantioselective transfer hydrogenation in thepresence of a chiral Ru(II)-complex leading to the compound of formula7, and coupling of the latter with the corresponding tosylate.

A family of asymmetric ferrocenyl hydrogenation catalysts such astransition metal complexes with the commercially availableTaniaphos-ligand(S)-1-dicyclohexylphosphino-2-[(S)-α-(dimethylamino)-2-(dicyclohexylphosphino)benzyl]-ferrocene(that is presently still incorrectly described as the(R)-1-dicyclohexylphosphino-2-[(S)-α-(dimethylamino)-2-(dicyclohexylphosphino)benzyl]-ferrocenein the commercial catalogue) was first described by T. Ireland et al. inAngew. Chem. J. Int. Ed. (1999), 38, 3212, although with an incorrectabsolute configuration regarding the ferrocenyl group that was believedto be (S) instead of (R). Similar compounds were disclosed shortlyafterwards in WO00/37478. Years later, Fukuzawa et al. (Eur. J. Org.Chem. (2007), 5540-5545) demonstrated that the ferrocenyl configurationreported in the article of T. Ireland et al. was incorrect and that theabsolute configuration of the ferrocenyl group was actually (R) and not(S), after which a corresponding corrigendum was published by T. Irelandet al. (Angew. Chem. J. Int. Ed. (2008), 47, 3666).

It has now surprisingly been found that compound of formula 7*acetatehas improved properties over the HCl analogue, and that compound offormula I can be manufactured in an improved way by the process of thepresent invention which uses asymmetric ferrocenyl hydrogenationcatalysts similar to those first described by T. Ireland et al. Furthersurprising technical effects are described in the description.

Various embodiments of the invention are presented hereafter:

i) the compound of formula 7*acetate

ii) a process for the preparation of the compound of formula 7*acetate

which process comprises the reaction of the compound of formula 7

with acetic acid, to obtain the compound of formula 7*acetate.

iii) a process according to embodiment ii), for the preparation of thecompound of formula 7*acetate, characterized in that the compound offormula 7

is prepared by hydrogenation of the compound of formula 4

in the presence of bis[chloro-1,5-cyclooctadiene-iridium],(S)-1-dicyclohexylphosphino-2-[(S)-α-(dimethylamino)-2-(dicyclohexylphosphino)benzyl]-ferrocene,iodine and a solvent, under hydrogen pressure of 1-200 bar, to obtainthe compound of formula 7.

iv) a process according to embodiment ii) or iii), for the preparationof the compound of formula 7*acetate, characterized in that the compoundof formula 4

is prepared by reaction of the compound of formula 4*mesylate

with a base, to obtain the compound of formula 4.

v) a process according to embodiment ii), wherein the reaction iscarried out with 0.9 to 1.3 equivalents of acetic acid.

vi) a process according to embodiment iii), wherein the amount of iodinecompared to the amount of Ir is between 0.2 and 10 mol equivalents.

vii) a process according to embodiment iii) or vi), wherein the molarratio between Ir and the chiral ligand is between 0.5:1 and 1:0.5.

viii) a process according to one of embodiments iii), vi) and vii),wherein the hydrogen pressure is between 1 and 50 bar.

ix) a process according to embodiment iv), wherein the amount of base isbetween 0.9 and 1.5 mol equivalents.

x) the use of compound of formula 7*acetate

for the preparation of the compound of formula I*HCl

The following paragraphs provide definitions of the various chemicalmoieties for the compounds according to the invention or of other termsused herein and are intended to apply uniformly throughout thespecification and claims, unless an otherwise expressly set outdefinition provides a different definition:

-   -   The term “C₁₋₄ aliphatic alcohol” as used herein denotes        straight or branched chain alkyl residues containing 1 to 4        carbon atoms with one hydroxy group, such as methanol, ethanol,        propanol, isopropanol, butanol, isobutanol or tert.-butanol.        Preferred C₁₄ aliphatic alcohols are methanol or ethanol.

The term “C₄₋₈ aliphatic hydrocarbon” as used herein denotes to straightor branched chain aliphatic hydrocarbons containing 4 to 8 carbon atoms,such as butane, isobutane, tert.-butane, pentane, hexane, heptane oroctane. The corresponding isomers are also encompassed by the term “C₄₋₈aliphatic hydrocarbon”.

Whenever the symbol “*” is followed by the expression “acetate”,“mesylate”, “HCl”, “CH₃SO₃H” or “CH₃COOH”, it denotes the correspondingsalt of the compound after which this combination is placed. Forexample, the expression “the compound of formula 7*acetate” denotes theacetate salt of the compound of formula 7.

-   -   The abbreviations “ee”, “mol %”, “wt %” and RT refer        respectively to the enantiomeric excess of an enantiomeric        mixture, to the molar percentage of a mixture, to the weight        percentage of a mixture and to room temperature.    -   The abbreviations “Ac” and “MI BK” refer respectively to the        acetyl group and to methylisobutylketone. “IPA” refers to        isopropanol, “MTBE” refers to methyl-tert.-butyl-ether, “DCM to        dichloromethane, “EtOAc” to ethylacetate.    -   Unless used regarding temperatures, the term “about” placed        before a numerical value “X” refers in the current application        to an interval extending from X minus 10% of X to X plus 10% of        X, and preferably to an interval extending from X minus 5% of X        to X plus 5% of X. In the particular case of temperatures, the        term “about” placed before a temperature “Y” refers in the        current application to an interval extending from the        temperature Y minus 10° C. to Y plus 10° C., and preferably to        an interval extending from Y minus 5° C. to Y plus 5° C.    -   For avoidance of any doubt, the denomination        3,4-dihydro-1H-isoquinoline (as used herein e.g. for compounds        of formula 7 or 1) and the denomination        1,2,3,4-tetrahydroisoquinoline as used herein refer to the same        structural entity.

The present invention is further described by reaction schemes 1-5.

In step a of the reaction, commercially available4-trifluoromethylcinnamic acid is hydrogenated in the presence of Pd/Cto obtain compound of formula I. Appropriate solvents are C₁₋₄ aliphaticalcohols and mixtures of C₁₋₄ aliphatic alcohols with water. Preferredsolvent is methanol. The hydrogenation may be carried out between 0.9 to15 bar, preferably at 2 bar, in the presence of 0.1 to 5 wt % (notably0.15 to 5 wt %) of a 5% Pd/C catalyst (preferably 2 wt % Pd/C, having 5%Pd on charcoal).

The reaction is carried out at a reaction temperature between 0° C., upto the corresponding boiling point of the respective solvent used,preferably between 15 to 50° C. (notably 15 to 25° C.).

In step b of the reaction, the compound of formula 1 is reacted withmethanol in the presence of an acid (such as p-toluene sulfonic acid,methanesulfonic acid or sulfuric acid, preferably in the presence ofsulfuric acid) to obtain the corresponding ester of formula 2.Preferably, the reaction is carried out in the presence of 5 mol %H₂SO₄, at a reaction temperature between 50 to 110° C. (notably 50 to80° C.) (preferably at the boiling point of the mixture). In a preferredembodiment of the reaction, the compound of formula 1 is not isolatedafter step a (only the catalyst is removed by filtration), and thereaction is continued with step b.

The technical advantage of step b, compared to the prior art, is that itcombines two chemical steps.

In step c of the reaction, compound of formula 2 is reacted withcommercially available 2-(3,4-dimethoxy-phenyl)-ethylamine in thepresence of an alcoholate, to obtain the compound of formula 3.Appropriate solvent for the reaction are aromatic boiling solvents (suchas benzene or a xylene), aliphatic hydrocarbons which are able to havean azeotrope with the corresponding alcohol (for example heptane). Apreferred solvent is toluene. The reaction is carried out at a reactiontemperature between 70 to 115° C., preferably at 110° C., in anotherembodiment preferably at 100° C. Suitable alcoholates (or alkoxides) arethose formed by the substitution of the hydrogen atom of the hydroxygroup of an alcohol by a metal atom. A preferred alcohol is the one usedfor the ester, and preferred metal atoms are Na, K or Li. An especiallypreferred alcoholate (or alkoxide) is sodium methoxide (preferablydissolved in methanol, such as 30% sodium methoxide in methanol).

The technical advantage of step c, compared to the prior art, is thatthe reaction is more stable, economical (direct coupling to the product;and no expensive coupling reagent is needed) and easy regarding the workup leading to the product.

In step d-1 of the reaction, the compound of formula 3 is reacted in thepresence of polyphosphoric acid or phosphorus oxychloride (preferablyphosphorus oxychloride in an amount of 0.5 to 1.5 equivalents (notably 1to 1.5 equivalents), in another embodiment 0.7 to 1.0 equivalents, perequivalent of compound of formula 3) to obtain the compound of formula4*HCl (said compound is a mixture of phosphorus imine salts and/orchlorophosphorous imine salts). Suitable solvents are aromatic solventssuch as benzene, xylene, mesitylene, or toluene (preferably toluene),and a suitable reaction temperature is between 60 to 120° C. (notably80-100° C.) (preferably 80-110° C.).

In step d-2 of the reaction, the reaction mixture of step d-1 is reactedwith a solution of an alkaline hydroxide (preferably a sodium hydroxidesolution), to obtain the compound of formula 4.

In step d-3 of the reaction, the reaction mixture of step d-2 is reactedwith methanesulfonic acid (preferably 0.9-1.5 equivalents; particularly1.0-1.2 equivalents) to obtain the compound of formula 4*mesylate. Thereaction is carried out at a reaction temperature from −5 to 60° C.(notably −5 to 40° C.), preferably between 0 to 40° C., in anotherembodiment preferably 0 to 10° C. Suitable solvent systems for thecrystallization of compound 4*mesylate are aromatic solvents (notablytoluene) and ketones (notably acetone) as well as mixtures thereof.

The compound of formula 4*mesylate is novel over the HCl analogue.

The technical advantages of step d-3, compared to the prior art, are thefollowing:

-   -   As the enantioselective hydrogenation is highly sensitive        towards impurities, high purity of the reactants is essential.        The surprising advantage of the 4*mesylate compound (as compared        to the HCl analogue) is that it precipitates in high purity,        notably from solvents like toluene, acetone or mixtures thereof.        As a consequence, the 4*mesylate can be subjected directly as        free amine into the enantioselective hydrogenation.    -   There is only one precipitation and isolation necessary yielding        to good product quality, and improvement of the process and        reduction of unit steps is achieved.

Additionally, the synthesis of main chain part 1 (reaction schemes 1 and2) was improved by reducing the number of solvents used.

In step e of the reaction, commercially available methylamine is reactedwith commercially available methyl (S)-mandelate to obtain the compoundof formula 5. In a preferred embodiment, the reaction is carried outwith 3 to 5 equivalents of methylamine (preferably 3.8 equivalents), andsaid methylamine is 30% in aqueous solution. The reaction is carried outat a reaction temperature from 5 to 35° C., preferably from 15 to 25° C.Alternatively, the reaction temperature may be from −5 to 35° C.,preferably from 0 to 10° C. After the reaction has been judged complete,excess methylamine may for example be distilled off at reduced pressure.

In step f of the reaction, the compound of formula 5 is reacted withp-toluene sulfonic acid chloride in the presence of a base such astriethylamine, pyridine or N-ethyldiisopropylamine (preferablyN-ethyldiisopropylamine), to obtain the compound of formula 6.Alternatively, a base like sodium hydroxide (preferably aqueous sodiumhydroxide) may be used.

In a preferred embodiment of the invention, after a solvent switch toethyl acetate the solution is concentrated, cooled to −2° C. and theprecipitate is filtered. Alternatively, toluene may be used in the aboveprocedure and the solution is cooled to −5 to 30° C. (notably 0 to 10°C.).

In a further preferred embodiment, the reaction is carried out with 1.0to 1.5 equivalents of p-toluene sulfonic acid chloride (preferably 1.0equivalent), and 1.05 to 3 equivalents of N-ethyldiisopropylamine(preferably 1.1 equivalents).

Suitable solvents are halogenated solvents, such as CHCl₃, CCl₄,dichloroethane, or dichloromethane (preferably dichloromethane).

The reaction is carried out at a reaction temperature from 0 to 35° C.(notably 5 to 30° C.), preferably below 25° C.

The technical advantages of step f, compared to the prior art, are thefollowing:

-   -   The coupling reaction was improved.    -   The overall process was improved with respect to product        quality.

In step g of the reaction, the compound of formula 4*mesylate is reactedwith a base (preferably an inorganic base such as sodiumhydrogenocarbonate or sodium hydroxide, more preferably sodiumhydroxide, especially an aqueous solution of sodium hydroxide) to obtainthe compound of formula 4. The amount of base for step g of the reactionmay be used in large ranges. Preferably, between 0.9 and 1.5 molequivalents of the corresponding base is used. Suitable solvents are anyorganic solvents (preferably a non-protic solvent; more preferred willbe a solvent which is used for the following step h, or following stepsh-1). Preferred solvents are C₁₋₄-alkyl acetates (wherein C₁₋₄-alkyl ismethyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert.-butyl,preferably methyl or ethyl, and most preferably ethyl). The reaction iscarried out at a reaction temperature between −10° C. and 80° C.,preferably between 10° C. and 50° C., and more preferably between 15° C.and 35° C. According to a preferred embodiment, activated charcoal (e.g.in an amount of up to 100 g per kg of compound of formula 4*mesylate) isadded to the reaction mixture and removed (e.g. by filtration) once thetreatment is completed.

In step h of the reaction, the compound of formula 4 is hydrogenatedusing hydrogen gas or a hydrogen transfer compound (e.g. isopropanol) inthe presence of a chiral catalyst (chiral hydrogenation catalyst ortransfer hydrogenation catalyst) and a solvent, and optionally in thepresence of an additive, to yield the compound of formula 7.

Said catalysts are commercially available, prepared beforehand, orprepared in situ, from any commercially available Ru, Ir and Rh complex(also known as precursors), and a commercially available chiral ligand,chiral ligands, or a combination of different ligands, of which one hasto be chiral. Suitable precursors are for examplebis(2-methylallyl)(1,5-cyclooctadiene)Ruthenium, [RuCl₂(p-cymene)]₂,bis(1,5-cyclooctadiene)Iridium tetrafluoroborate,bis[chloro-1,5-cyclooctadiene-iridium], and bis(cyclooctadiene)Rhodiumtetrafluoroborate. Preferred precursors are Ir-based precursors(Ru-based and Ir based precursors for the transferhydrogenation).

Suitable chiral ligands are known by the person skilled in the art, andare for example described in the Handbook of Homogeneous Hydrogenation,J. G de Vries, C. J., Elsevier, Eds.; Wiley, 2007, chapter 23-35.Preferred chiral ligands are chiral bisphosphine ligands, and chiralmonodentate phosphor containing ligands, amines, aminoalcohols orbisamines.

Suitable chiral ligands are for example the bisphosphines, such JosiPhostype ligands; MandyPhos; TaniaPhos type of ligands; BINAP, and itsanalogues, DUPhos; Chiraphos; and monodentate ligands such the MonoPhostype ligands, for example(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yl)dimethylamine(MonoPhos).

Preferably the chiral ligand is the commercially availableTaniaphos-ligand(S)-1-dicyclohexylphosphino-2-[(S)-α-(dimethylamino)-2-(dicyclohexylphosphino)benzyl]-ferrocene.

Suitable non chiral ligands are dienes, amines, alcohols or phosphines.

If the chiral catalyst is prepared beforehand or in situ, the amount ofchiral ligand is between 0.25 and 6 mol equivalents compared to the molamount of metal precursor, preferably between 0.5 and 2 mol equivalents.

An additive is a compound added to the reaction mixture to enhance thehydrogenation rate, and/or increase the enantioselectivity. Suitableadditives are organic and inorganic compounds, for example halogens(e.g. iodine), halogen containing compounds, bases, or acids. Suitableexamples are iodine, potassium tert-butoxide, phthalimide, acetic acidor benzoic acid. Preferably 12 is used as additive in combination withan Ir-based chiral catalyst.

The amount of additive used in the preparation of the chiralhydrogenation catalyst of the invention is depending on the additiveused, but is in general between 0.2 and 100 equivalents compared to themol amount of metal used, preferably the amount of additive is between 1and 50 mol equivalents, most preferably the amount of additive isbetween 1 and 10 mol equivalents compared with the mol amount of metalused.

The preferred chiral catalyst of the invention is prepared from asuitable Ir-precursor, the TaniaPhos ligand described above, and iodineas additive. The preferred amount of TaniaPhos ligand, is between 0.5and 1.5 mol equivalents compared to the mol amount of Ir and thepreferred amount of 12 (as additive) is between 1 and 3 mol equivalentscompared to the mol amount of Ir. In a further embodiment of theinvention the molar ratio between Ir and the chiral ligand is between0.5:1 and 1:0.5.

Any solvent could be used for the hydrogenation reaction. Preferred arepolar solvents, for example isopropanol, methanol, ethylacetate, MIBK,dichloromethane, and toluene, or any combination thereof.

The amount of catalyst compared with the amount of substrate ispreferably as low as possible. In practice molar substrate catalystratio's are exceeding 100, and more preferably are exceeding 500 or1000.

In one aspect of the invention, the hydrogenation catalyst is preparedbeforehand, by mixing the metal precursor, the chiral ligand or chiralligands or mixture of ligands, in a suitable solvent and optionally anadditive.

The preparation of the catalyst is preferably done in a polar solvent. Asuitable solvent is methanol, dichloromethane or a mixture of methanoland dichloromethane (notably dichloromethane).

The catalyst preparation is carried out at a reaction temperaturebetween −10° C. and 80° C., preferably between 10° C. and 50° C. andmore preferably between 15° C. and 25° C.

After preparation of the catalyst, the solution as such is added to thesubstrate solution, or the solvent used for the catalyst preparation isfirst evaporated and the catalyst is dissolved in the solvent of choicefor the hydrogenation.

The preferred chiral catalyst of the invention is prepared beforehandfrom a suitable Ir-precursor, the TaniaPhos ligand described above, andiodine as additive in dichloromethane as solvent. The amount ofTaniaPhos ligand is between 0.5 and 1.5 mol equivalents compared to themol amount of Ir and the amount of 12 (as additive) is between 1 and 3mol equivalents compared to the mol amount of Ir.

The hydrogenation is carried out with a transfer hydrogenation compound,for example isopropanol, or in the presence of hydrogen gas. Suitablehydrogen pressures are between 1 and 200 bar, preferably between 1 and50 bar and more preferably between 1 and 10 bar.

The hydrogenation reaction is carried out at a temperature between −10°C. and 100° C., preferably between 10° C. and 75° C. and more preferablybetween 15 and 35° C. A temperature regime of first performing thehydrogenation at 15° C. and subsequent increase during hydrogenationincreases the speed of conversion and ee of the product.

The technical advantages of step h, compared to the prior art, are thefollowing:

-   -   Different chiral catalyst systems have been tested for the        enantioselective hydrogenation of compound of formula 4. It has        been found that only the Taniaphos catalyst shows a surprisingly        high ee of 92-95%.    -   Compared to the racemic resolution, the novel enantioselective        hydrogenation prevents the tedious separation of the enantiomers        via diastereomeric salt formation and recycling of the wrong        enantiomer.    -   Compared to the Noyori transfer hydrogenation catalyst, the        enantioselective hydrogenation with the Taniaphos catalyst shows        a surprisingly high ee of 92-95%.    -   Additionally, in large scale quantities, the enantioselective        hydrogenation with the Taniaphos catalyst shows a more stable ee        (as compared to the with the Noyori transfer hydrogenation        catalyst).

In another aspect of the invention, the compound of formula 4*CH₃SO₃H ishydrogenated in the presence of a chiral catalyst and a solvent asdescribed above, and in the presence of a base, and optionally in thepresence of an additive as described above. In this aspect of theinvention step g and step h are performed simultaneously.

Suitable bases for this aspect of the invention are any base compatiblewith the hydrogenation catalyst. Suitable bases are for example primary,secondary and tertiary amines, and compounds containingN,N-dialkylamine-groups, such as Et₃N, and iPr₂NEt. The amount of basemay vary within a large range, preferably a catalytically amount of baseis used, such as 0.1 equivalent compared with the compound of formula4*CH₃SO₃H.

In step l of the reaction, the compound of formula 7 is reacted withacetic acid, to obtain the compound of formula 7*acetate.

The reaction is carried out in a suitable solvent, such as any aromaticsolvent or mixture of aromatic solvents (such as benzene, toluene and/orxylene) and aliphatic hydrocarbons (preferably a C₄₋₈ aliphatichydrocarbon, or any mixture thereof, or distillation fractionscontaining mainly heptane). A preferred solvent mixture is toluene andheptane with pure toluene and heptane or mixtures thereof. Morepreferred is a 4 to 1 mixture of toluene and heptane.

The reaction is carried out at a reaction temperature between −10 to 55°C. preferably between 0 and 20° C.

The reaction is carried out with 0.9 to 1.3 equivalents of acetic acid,more preferred with 1.0 equivalent of acetic acid.

Due to the unfavourable compound properties of enantiomeric6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride, the enantiomeric pure synthesis is limited.

It was now surprisingly found that, the acetate salt of6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-1,2,3,4-tetrahydro-isoquinoline(compound 7*acetate) has improved compound properties, that enables theenantiomeric pure synthesis. Additionally, based on the improvedcompound properties of the compound 7*acetate a more completecrystallisation of the acetate salt is achieved, and therefore a higheryield is obtained.

The eutectics were surprisingly shifted by the choice of a suitable acidand solvent (aromatic solvent, e.g. toluene) towards the desireddirection.

In step j of the reaction, the compound of formula 7*acetate is reactedwith a base (preferably an inorganic base such as sodium hydroxide, morepreferably an aqueous solution of sodium hydroxide) to obtain thecompound of formula 7. In a preferred embodiment, the reaction iscarried out with an aqueous solution of sodium hydroxide (preferably asodium hydroxide solution which is 20%). Suitable solvents are ketones(such as acetone, ethyl methyl ketone, t-butyl methyl ether, CH₂Cl₂,MIBK, preferably MIBK). The reaction is carried out at a reactiontemperature between 0-50° C., preferably between 15-25° C.

The technical advantage of step j, compared to the prior art, is e.g.the efficient use of MIBK as solvent.

In step k of the reaction, the compound of formula 7 is reacted withcompound of formula 6, in the presence of a base to obtain the compoundof formula 1. In a preferred embodiment, the reaction is carried outwith 1.1-2.0 equivalents (preferably 1.2 equivalents) of compound offormula 6. Appropriate bases are Li₂CO₃, Cs₂CO₃, the correspondingbicarbonates, caustic soda, potassium carbonate, and mixtures thereof.In a preferred embodiment of the invention, mixtures of the beforementioned bases are used. In a further preferred embodiment, causticsoda is used in an amount of 0-2.2 equivalents (more preferred 1.2equivalents of caustic soda), and potassium carbonate is used in anamount of 0-2.2 equivalents (more preferred 1.2 equivalents of potassiumcarbonate). Suitable solvents are MIBK, MTBE or CH₂Cl₂ (preferablyMIBK). The reaction is carried out at a reaction temperature between30-120° C., preferably between 70-90° C.

The technical advantage of step k, compared to the prior art, is thatthe coupling reaction could surprisingly be performed at higherconcentrations.

In step l of the reaction, the compound of formula I is reacted withhydrochloric acid, to obtain compound of formula I*HCl. In a preferredembodiment, the reaction is carried out with 0.95-1.1 equivalents(preferably 1.0 equivalent) of aqueous hydrochloric acid.

The technical advantages of step 1, compared to the prior art, are:

-   -   It is surprising that the HCl salt of the compound of formula I        is obtained from compound of formula I in the presence of        aqueous hydrochloric acid without significant amount of        hydrolysis (hydrolysis less than 0.5%).    -   Furthermore the synthesis was simplified by the use of aqueous        hydrochloric acid for the precipitation of the active        pharmaceutical ingredient and subsequent azeotropic removal of        water.

EXPERIMENTAL PART

Particular embodiments of the invention are described in the followingexamples, which serve to illustrate the invention in more detail withoutlimiting its scope in any way.

Step 1: synthesis of 3-(4-trifluoromethyl-phenyl)-propionic acid(compound 1)

A solution of 4-trifluoromethylcinnamic acid (commercial available) inmethanol is hydrogenated with Pd/C (5 wt %) at 2 bar until4-trifluoromethylcinnamic acid has reacted completely. After removal ofthe catalyst by filtration the 4-trifluoromethylhydrocinnamic acid isfurther reacted in step 2 to compound 2.

Step 2: synthesis of 3-(4-trifluoromethyl-phenyl)-propionic acid methylester (compound 2)

To the methanolic reaction mixture obtained from step 1 is added 5 mol %sulfuric acid and the mixture is heated. The formed water is distilledoff until the esterification is complete. Then, methanol is completelyremoved.

Step 3: synthesis ofN-[2-(3,4-dimethoxy-phenyl)-ethyl]-3-(4-trifluoromethyl-phenyl)-propionamide(compound 3)

3-(4-trifluoromethyl-phenyl)-propionic acid methyl ester is dissolved intoluene, 1.05 equivalents 2-(3,4-dimethoxy-phenyl)-ethylamine(commercially available) and 1.1 equivalents sodium methoxide (30% inmethanol) are added. At normal pressure the reaction mixture is heatedto a maximum of 110° C. and methanol distilled until full conversion isreached. The reaction mixture is washed with water and sulfuric acid.During cooling of the organic phase, the compound 3 crystallises and isfiltered, washed with cold toluene and dried in vacuo at 50° C.

Step 4: synthesis of6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-isoquinolinemethanesulfonic acid (compound 4*mesylate)

The compound 3 is suspended in toluene and heated to 80-100° C. Afteraddition of 1.5 equivalents phosphorus oxychloride the mixture is heatedfor 6 hours to 80-100° C. and then cooled within 3 hours to 20° C. Thesuspension is added to water while maintaining the pH of the aqueouslayer during addition and subsequent stirring between 7-8 by addition ofa sodium hydroxide solution. The mixture is stirred until allprecipitate is dissolved. After phase separation the water is removed byazeotropic distillation. Then 1.0 equivalent of methanesulfonic acid isadded and the formed suspension stirred for some time. At this point intime parts of the solvent may be replaced by acetone, and then themixture is slowly cooled to 0-10° C. and stirred at this temperature foranother couple of hours. After filtration the product is washed withtoluene and dried in vacuo.

Step 5: synthesis of (S)-mandelamid (compound 5)

To a solution of methylamine (40% in water, 3.8 equivalents) is added,at ambient temperature, methyl (S)-mandelate (1.0 equivalent;commercially available), while keeping the temperature below 30° C. andstirred at ambient temperature until full conversion is achieved. Excessmethylamine is removed by azeotropic distillation. Alternatively, afterneutralisation with aqueous hydrochloric acid the aqueous solution issaturated with sodium chloride and extracted several times withdichloromethane. The organic layers are combined and the water isremoved by azeotropic distillation.

Step 6: synthesis of (S)-toluene-4-sulfonic acidmethylcarbamoyl-phenyl-methyl ester (compound 6)

To the solution of mandelic acid amide in dichloromethane is addedN-ethyldiisopropylamine (1.1 equivalents) at RT. Subsequently p-toluenesulfonic acid chloride (1.0 equivalent) is added keeping the temperaturebelow 25° C. The reaction mixture is stirred at RT until a satisfactoryconversion is reached and then washed with saturated sodium bicarbonatesolution und water. After a solvent switch to ethyl acetate the solutionis concentrated, cooled to −2° C. and the precipitate filtered. Thecrystals are washed with cooled ethyl acetate and dried in vacuo at 40°C.

Alternatively, to the solution of mandelic acid amide in dichloromethaneis added 50% aqueous caustic soda at RT. Subsequently p-toluene sulfonicacid chloride (1.0 equivalent) is added as a solution in dichloromethanekeeping the temperature below 25° C. The biphasic reaction mixture isstirred at RT until a satisfactory conversion is reached, phases areseparated, the aqueous phase is extracted once with dichloromethane andthen the combined organic phases are washed with water. After a solventswitch to toluene the solution is concentrated, cooled to 5° C. and theprecipitate filtered. The crystals are washed with cooled toluene anddried in vacuo at 40° C.

Step 7: synthesis of6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-isoquinoline(compound 4)

Method A:

To a suspension of 4*mesylate in ethyl acetate is added sodium hydroxidesolution and stirred at RT until the precipitate is dissolved. Afterphase separation the aqueous phase is extracted a second time with ethylacetate. The combined organic extracts are treated with charcoal andfiltered. After removal of the water by azeotropic distillation thesolution is diluted with ethyl acetate to a concentration of 5-6%.

Method B:

4*mesylate is added to a mixture of water and a 4:1 mixture oftoluene/heptane (or, alternatively, to a mixture of water and toluene).The system is stirred until solids are dissolved. Aqueous caustic sodais then added, the mixture is stirred at RT, and phases are separated.The organic layer is washed several times with water and aqueous streamsare discarded. Charcoal is charged to the solution of free imine 4,stirred, and the mixture is dried by azeotropic distillation. Afterremoval of the water, the charcoal is removed by filtration, and theconcentration of the solution is adjusted to 10-15%.

Method C:

To 4*mesylate (51.9 g; 0.113 mol) is added water (110 mL). The mixtureis stirred for 30 min and toluene (500 mL) is added. Aqueous causticsoda (20 wt %; 110 mL) is then added. Toluene (600 mL) is then added andthe phases are separated. The organic layer is washed four times withwater (110 mL) and aqueous streams are discarded. The pH value of theaqueous phase should in the end be 7. Charcoal (Norix® SX Plus; 1.61 g)is added to the solution of free imine 4 which is then stirred for 1 hat RT. After filtration, the organic phase is washed with toluene (550mL) and concentrated to a volume of 200-300 mL (70 mbar, 40° C.).Toluene (100 mL) is added and the organic phase is concentrated to avolume of about 120 mL (70 mbar, 40° C.). The appropriate volume oftoluene to obtain the desired concentration of imine 4 is added and Aris then bubbled through the imine solution for 30 min.

Step 8: synthesis of(1S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1H-isoquinoline(compound 7)

Taniaphos Ligand:

Method A:

To a solution of bis[chloro-1,5-cyclooctadiene-iridium] (commerciallyavailable) in degassed dichloromethane is added at 20° C.(S)-1-dicyclohexylphosphino-2-[(S)-α-(dimethylamino)-2-(dicyclohexylphosphino)benzyl]-ferrocene(the Taniaphos-ligand is commercially available or may be synthesizedaccording to Angew. Chem. J. Int. Ed. (1999), 38, 3212). Subsequently asolution of iodine in degassed dichloromethane is added and theresulting solution is stirred until the formed precipitate is dissolved.The solution of the catalyst precursor is added to the imine solution ofstep 7 and hydrogenated at 5 bar H₂ pressure and 30° C.

Examples 1-6 Made According to Method A

Ex. No. I₂/Ir Substrate/Catalyst Conversion [%] ee [%] 1 1 200 99 73 2 120 100 89 3 2 200 100 95 4 2 20 100 95 5 4 200 100 86 6 4 20 100 92

Further experiments have been carried out at I₂/Ir ratio of 2 withincreasing substrate to catalyst ratio (from 300 to 750), and the ee'sremain between 94 and 95%.

Various other transition metal/chiral ligand systems in differentsolvents (such as HOAc, MeOH, DCM, IPA, toluene, Ac₂O, EtOAc, CH₃CN,MTBE, 2-butanone, DMF or DCM/HOAc (50:1)) have been tested to convertthe compound of formula 4 into the compound of formula 7 viaenantioselective hydrogenation. Transition metals tested include Ir(e.g. in the form of [Ir(COD)Cl]₂), and Rh (e.g. in the form of[Rh(COD)₂BF₄). For example the following chiral ligands have beentested:

With the above mentioned transition metal/chiral ligand systems, thecombination of high ee's in combination with high conversion rates couldnot be achieved.

Method B:

To a solution of bis[chloro-1,5-cyclooctadiene-iridium] (commerciallyavailable) in a degassed mixture of dichloromethane and methanol isadded at 20° C.(R)-1-dicyclohexylphosphino-2-[(S)-α-(dimethylamino)-2-(dicyclohexylphosphino)benzyl]-ferrocene(the Taniaphos-ligand is commercially available or may be synthesizedaccording to Angew. Chem. J. Int. Ed. (1999), 38, 3212). Subsequently, asolution of iodine in a degassed mixture of dichloromethane and methanolis added and the resulting solution is stirred until the formedprecipitate is dissolved. The solution of the catalyst preparation isadded to the imine solution of step 7, METHOD B, and hydrogenated at 5bar (3-10 bar) H₂ pressure and at 20° C. (10-30° C.).

Examples 7-8 Made According to Method B

Solvent system ee after ee after Ex. for the Substrate/ Conversionreaction work-up No. I₂/Ir compound 4 Catalyst [%] [%] [%] 7 2 toluene/1500 98 91 99 heptane 4:1 8 2 toluene 1500 98 88 99

Further experiments have been carried out at I₂/Ir ratio of 2 withincreasing substrate to catalyst ratio (from 1000 to 2000), and typicalee's are between 88 and 95%.

Method C:

To bis[chloro-1,5-cyclooctadiene-iridium] (commercially available; 13.5mg; 0.02 mmol) is added(R)-1-dicyclohexylphosphino-2-[(S)-α-(dimethylamino)-2-(dicyclohexylphosphino)benzyl]-ferrocene(30.5 mg; 0.042 mmol; the Taniaphos-ligand is commercially available ormay be synthesized according to Angew. Chem. J. Int. Ed. (1999), 38,3212). The mixture is placed under high vacuum conditions (1-2 mbar),then put under argon atmosphere (1 bar), this procedure (vacuum thenargon atmosphere) being repeated 4 times. The mixture is kept underargon atmosphere and degassed methanol is added. After three hoursstirring at RT, a red clear solution is obtained. Solid iodine is addedand the resulting solution is stirred for 30 min. The solvent is thenremoved (1 mbar, RT) and the solid residue is dried for 30 min (1 mbar,RT). 1,2-dichloroethane (DCE) is added to the solid under argon,yielding the catalyst solution. Depending on the reaction solventsystem, the solution of imine 4 (obtained at step 7, METHOD C) intoluene (Tol) is mixed with the appropriate volume of hexane (Hex),heptane (Hept) or tetrahydrofuran (THF) and the catalyst solution in DCEpreviously obtained is added. The volume of Tol used for the imine 4,the volume of DCE used for the catalyst solution and the volume ofhexane (Hex), heptane (Hept) or tetrahydrofuran (THF) added are suchthat they make together the reaction solvent system. The reactionmixture is put under H₂ pressure (5 bar) at the temperature T, thereaction being completed after a certain time t_(R). Details of thevarious experiments carried out are summarized in the table hereafter.

Examples 9-17 Made According to Method C

Quantity of Reaction Solvent I₂/Ir Ex. imine 4 solvent volume ratio TSubstrate/ Conversion ee t_(R) No. [mmol] system [mL] [eq./eq.] [° C.]Catalyst [%] [%] [min]  9^(a,b) 7.5 Tol/THF/DCE 24 3 RT 1000 100 97 309/2/1 10^(a) 7.5 Tol/Hex/DCE 24 3 RT 2000 99 95 15 9/2/1 11^(c) 10Tol/THF/DCE 24 4 RT 2000 94 95 120 9/2/1 12 11.3 Tol/Hex/DCE 28 3 163000 99.5 96 90 9/2/1 13 11.3 Tol/Hex/DCE 28 3 16 4000 95 95 80 9/2/1 1419 Tol/Hex/DCE 85 3 16 3000 99.3 95.7 45 9/2/1 15 11.3 Tol/Hex/DCE 27 316 4000 95.6 95.3 150 9/2/1 16^(d) 38 Tol/Hex/DCE 91 3 16 2500 100 95.229 9/2/1 17 38 Tol/Hept/DCE 119 3 16 3000 98.8 95.0 60 13/4/1 ^(a)Forthis experiment, the imine 4 was prepared using the protocol of step 7,METHOD B, the imine solution being however dried by the use of Na₂SO₄^(b)In this experiment, the catalyst was stirred with methanol for onehour only (not three). ^(c)In this experiment, after the methanolremoval from the catalyst, toluene was added to the catalyst which wasthen removed ^(d)In this experiment, the catalyst was stored one dayafter its preparation before being used

Step 7 and 8 simultaneously.

To a suspension of 4*mesylate in ethyl acetate is addedbis[chloro-1,5-cyclooctadiene-iridium], a suitable amount of the ligandB as depicted above, and iPr₂NEt. The mixture is warmed to 50° C., and25 bar of H₂ pressure is applied.

Step 9: synthesis of(1S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolineacetic acid (compound 7*acetic acid)

Method A:

After full conversion a solvent switch to toluene is performed. Thenheptanes are added to reach a ratio of toluene/heptanes of 4 to 1. Byaddition of 1.0 equivalent of acetic acid compound 7*acetic acid isprecipitated at 20° C. The suspension is aged at RT to ensure completeprecipitation, filtered and washed with heptanes. The product is driedin vacuo at 40° C.

Method B:

After full conversion, the residual solvents dichloromethane andmethanol from the catalyst preparation are removed by distillation,resulting in a solution of amine 7 in toluene, respectively atoluene/heptane mixture. By addition of 1.0 equivalent acetic acid,compound 7*acetic acid is precipitated at 20° C. The suspension is agedat RT (0-20° C.) to ensure complete precipitation, filtered and washedwith toluene, respectively a mixture of toluene/heptanes. The product isdried in vacuo at 40° C. By application of this method the opticalpurity of the product can be increased even from 81% ee afterhydrogenation up to 99% ee in the isolated material.

Step 10: synthesis of(1S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1H-isoquinoline(compound 7)

To a suspension of compound 7*acetic acid in MIBK is added sodiumhydroxide solution (20%) and stirred at RT until the precipitate isdissolved. After phase separation, the organic layer is washed withwater. After removal of the water from the organic phase by azeotropicdistillation, the solution is diluted with MIBK to a concentration of9-16%.

Step 11: synthesis of(2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-N-methyl-2-phenyl-acetamide(compound I)

To the solution of the compound 7 in MIBK are added 1.2 equivalents ofthe compound 6, 1.1 equivalents caustic soda and 1.1 equivalentspotassium carbonate and heated to 70-90° C. Water is added and themixture is heated at the same temperature for 0.5 to 3 hours and thencooled to RT. Alternatively, after full conversion the solution iscooled to RT and water is added. Phase separation is followed by asecond washing of the organic phase with water and again phaseseparation.

Step 12: synthesis of(2R)-2-(1S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl)N-methyl-2-phenyl-acetamidehydrochloride (compound I hydrochloride)

To the organic phase of step 11 is added 1 equivalent aqueoushydrochloric acid and then the water removed by azeotropic distillationin vacuo.

Then, either:

-   -   The precipitate is dissolved by addition of 2-propanol at 75° C.        Concentration of the solution leads to crystallisation and the        suspension is then cooled to RT. To ensure complete        crystallisation, the suspension is aged at RT, then filtered and        washed with a MIBK-2-propanol mixture. or:    -   the compound I*HCl is obtained by crystallization from the        organic phase of step 11 (MIBK) containing an adjusted amount of        residual water (0.4-1.5%, e.g. 0.7%) without using 2-propanol at        a temperature of above 40° C. (e.g. about 65° C.) using seeding        crystals.

The product is isolated e.g. on an inverting bag centrifuge and dried invacuo at 50° C.

1. Compound of formula 7*acetate


2. Process for the preparation of the compound of formula 7*acetate

which process comprises the reaction of the compound of formula 7

with acetic acid, to obtain the compound of formula 7*acetate.
 3. Process according to claim 2, for the preparation of the compound of formula 7*acetate, characterized in that the compound of formula 7

is prepared by hydrogenation of the compound of formula 4

in the presence of bis[chloro-1,5-cyclooctadiene-iridium], (S)-1-dicyclohexylphosphino-2-[(S)-α-(dimethylamino)-2-(dicyclohexylphosphino)benzyl]-ferrocene, iodine and a solvent, under hydrogen pressure of 1-200 bar, to obtain the compound of formula
 7. 4. Process according to claim 2, for the preparation of the compound of formula 7*acetate, characterized in that the compound of formula 4

is prepared by reaction of the compound of formula 4*mesylate

with a base, to obtain the compound of formula
 4. 5. Process according to claim 2, wherein the reaction is carried out with 0.9 to 1.3 equivalents of acetic acid.
 6. Process according to claim 3, wherein the amount of iodine compared to the amount of Ir is between 0.2 and 10 mol equivalents.
 7. Process according to claim 3, wherein the molar ratio between Ir and the chiral ligand is between 0.5:1 and 1:0.5.
 8. Process according to claim 3 wherein the hydrogen pressure is between 1 and 50 bar.
 9. Process according to claim 4, wherein the amount of base is between 0.9 and 1.5 mol equivalents.
 10. Use of the compound of formula 7*acetate

for the preparation of compound of formula I*HCl 